Bone loss occuring with unloading is associated with decreased osteoblastogenesis and increased bone marrow adipogenesis, resulting in bone loss and decreased bone formation. Here, we review the present knowledge on the role of PPARγ in the control of osteoblastogenesis and bone mass in skeletal unloading. We showed that PPARγ positively promotes adipogenesis and negatively regulates osteoblast differentiation of bone marrow stromal cells in unloading, resulting in bone loss. Manipulation of PPARγ2 expression by exogenous TGF-β2 inhibits the exaggerated adipogenesis and corrects the balance between osteoblastogenesis and adipogenesis induced by unloading, leading to prevention of bone loss. This shows that PPARγ plays an important role in the control of bone mass in unloaded bone. Moreover, this opens the possibility that manipulation of PPARγ may correct the balance between osteoblastogenesis and adipogenesis and prevent bone loss, which may have potential implications in the treatment of bone loss in clinical conditions.